PROJECT SUMMARY/ABSTRACT The condition of being overweight or obese has been implicated as a risk factor for breast cancer. According to the National Center for Health Statistics (NCHS), ~42.3% of women ages 50 and older in US are obese whose breast cancer risk is increased two- to four- fold. Furthermore, the current pandemic of obesity can potentially lead to a corresponding increase in breast cancer world-wide. There is a clear and compelling need to develop chemopreventive strategies to combat breast cancer in obese population. With an overall goal to develop effective chemopreventive strategies to target breast cancer in obese state, in this proposal, we will examine the molecular mechanism(s) whereby Benzyl isothiocyanate (BITC), a bioactive compound derived from cruciferous vegetables, prevents breast cancer growth in obese hyperleptinemic conditions. Research from our lab and others has shown that high leptin levels (hyperleptinemia) associated with obese state is a major driver of breast cancer progression and metastasis. Examining bioactive approaches to block leptin signaling, we recently discovered that BITC can effectively reduce leptin-induced proliferation and blocks leptin-induced migration potential of breast cancer cells. The project consists of two highly innovative aims. Aim 1 will test whether BITC blocks leptin-induced epithelial-mesenchymal transition, inhibits leptin-signaling network and examine the role of miR-34a in mediating BITC actions. Our studies will establish BITC as an effective leptin- antagonist and dissect the underlying molecular interactions between BITC and leptin signaling axes potentially revealing new crosstalk. Aim 2 will focus on examining whether BITC impedes paracrine actions of leptin and prevents breast carcinogenesis in hyperleptinemic obese state. Our preliminary findings show that the paracrine effect of leptin is important for adipocytes-breast cancer cells crosstalk leading to induction of EMT, invasion and migration potential of breast cancer cells. Results from this aim will decipher if BITC can block paracrine effects of leptin and prevent adipocytes-breast cancer cells crosstalk outcome. Our studies will advance the BITC chemoprevention field in a new direction showing the effectiveness of BITC in preventing breast cancer progression in obese conditions and establishing BITC as a novel leptin-antagonist. These studies will provide pre-clinical information to design clinical trials of BITC-based chemopreventive strategies for obese persons at high risk for developing breast cancer. It is important to note that obesity is attributed to ~90,000 cancer-related deaths/year in the USA therefore our findings will have far-reaching impact.